Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Regulation of ion transport proteins by membrane phosphoinositides

Key Points

  • Over the past decade, a wide variety of ion channels and transporter proteins have been shown to be sensitive to the abundance of phosphoinositides in the plasma membrane. The regulated transport proteins include K+ and Ca2+ channels, transient receptor potential (TRP) channels, transporters, exchangers and others. Most of the regulation is mediated specifically by phosphatidylinositol-4,5-bisphosphate (PIP2), although other signals use other specific phosphoinositides.

  • The response to phosphoinositide-mediated signals is determined by the affinity of the channel or transporter for the lipid, with high affinity channels often being constitutively active and least sensitive, and low affinity channels often being constitutively inactive and most sensitive.

  • For PIP2-mediated signals, the action is thought to involve binding or unbinding of the anionic lipids to the channel or transporter at domains containing basic residues that are thought to be in proximity to the inner leaflet of the membrane.

  • The binding or unbinding can be in response to either an altered abundance of membrane phosphoinositide or to an altered affinity of the channel or transporter for the phosphoinositide. For receptors coupled to G proteins, the physiological signal can be depletion of PIP2, or it can be the production or activation of some other downstream molecule (for example, Gβγ subunits, protein kinase C or calmodulin) that alters the PIP2 affinity.

  • The ubiquity of channel or transporter sensitivity to phosphoinositide abundance necessitates the existence of mechanisms that can achieve specificity and fidelity in signalling. These mechanisms might include the clustering of receptors, channels and signalling molecules into microdomains, the restriction of the mobility of phosphoinositides in the membrane, the local aggregation of phosphoinositides by specific sequestration proteins, and the detection by the channels or transporters of multiple simultaneous signalling events.

Abstract

Over the past decade, there has been an explosion in the number of membrane transport proteins that have been shown to be sensitive to the abundance of phosphoinositides in the plasma membrane. These proteins include voltage-gated potassium and calcium channels, ion channels that mediate sensory and nociceptive responses, epithelial transport proteins and ionic exchangers. Each of the regulatory lipids is also under multifaceted regulatory control. Phosphoinositide modulation of membrane proteins in neurons often has a dramatic effect on neuronal excitability and synaptic transmitter release. The repertoire of lipid signalling mechanisms that regulate membrane proteins is intriguingly complex and provides a rich array of topics for neuroscience research.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The regulation of membrane proteins by PIP2.
Figure 2: PIP2 sensitivity of K+ channels.
Figure 3: The PIP2 sensitivity of N-type Ca2+ channels.
Figure 4: The PIP2 sensitivity and putative PIP2-binding domains of transient receptor potential (TRP) channels.

Similar content being viewed by others

References

  1. Nichols, C. G. & Lopatin, A. N. Inward rectifier potassium channels. Annu. Rev. Physiol. 59, 171–191 (1997).

    CAS  PubMed  Google Scholar 

  2. Logothetis, D. E., Jin, T., Lupyan, D. & Rosenhouse-Dantsker, A. Phosphoinositide-mediated gating of inwardly rectifying K+ channels. Pflugers Arch. 455, 83–95 (2007).

    CAS  PubMed  Google Scholar 

  3. Logothetis, D. E., Lupyan, D. & Rosenhouse-Dantsker, A. Diverse Kir modulators act in close proximity to residues implicated in phosphoinositide binding. J. Physiol. (Lond.) 582, 953–965 (2007).

    CAS  Google Scholar 

  4. Ruppersberg, J. P. Intracellular regulation of inward rectifier K+ channels. Pflugers Arch. 441, 1–11 (2000).

    CAS  PubMed  Google Scholar 

  5. Stanfield, P. R., Nakajima, S. & Nakajima, Y. Constitutively active and G-protein coupled inward rectifier K+ channels: Kir2.0 and Kir3.0. Rev. Physiol. Biochem. Pharmacol. 145, 47–179 (2002).

    CAS  PubMed  Google Scholar 

  6. Takano, M. & Kuratomi, S. Regulation of cardiac inwardly rectifying potassium channels by membrane lipid metabolism. Prog. Biophys. Mol. Biol. 81, 67–79 (2003).

    CAS  PubMed  Google Scholar 

  7. Xie, L. H., John, S. A., Ribalet, B. & Weiss, J. N. Activation of inwardly rectifying potassium (Kir) channels by phosphatidylinositol-4,5-bisphosphate (PIP2): interaction with other regulatory ligands. Prog. Biophys. Mol. Biol. 94, 320–335 (2007).

    CAS  PubMed  Google Scholar 

  8. Hilgemann, D. W. & Ball, R. Regulation of cardiac Na+, Ca2+ exchange and KATP potassium channels by PIP2 . Science 273, 956–959 (1996). This study provided the first electrophysiological demonstration of the sensitivity of membrane transport proteins to membrane phosphoinositides.

    CAS  PubMed  Google Scholar 

  9. Fan, Z. & Makielski, J. C. Anionic phospholipids activate ATP-sensitive potassium channels. J. Biol. Chem. 272, 5388–5395 (1997). In this study, the authors showed that K ATP channels require the presence of anionic phospholipids.

    CAS  PubMed  Google Scholar 

  10. Huang, C. L., Feng, S. & Hilgemann, D. W. Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gβγ . Nature 391, 803–806 (1998). This paper provided the first demonstration of the dependence of diverse Kir channels on PIP 2 , and of their binding; of the importance of C-terminal basic residues in the interaction; and of the proposed mechanism of G βγ activation of GIRK channels by stabilization of channel–PIP 2 interactions. The paradigms that were used here serve as templates for ongoing work.

    CAS  PubMed  Google Scholar 

  11. Shyng, S. L. & Nichols, C. G. Membrane phospholipid control of nucleotide sensitivity of KATP channels. Science 282, 1138–1141 (1998).

    CAS  PubMed  Google Scholar 

  12. Zhang, H., He, C., Yan, X., Mirshahi, T. & Logothetis, D. E. Activation of inwardly rectifying K+ channels by distinct PtdIns(4,5)P2 interactions. Nature Cell Biol. 1, 183–188 (1999). This paper proposed that the constitutive nature of IRK channels and the G-protein-activated nature of GIRK channels are a result of their differential apparent affinity for PIP 2 . It also identified the critical C-terminal domain that conferrs the differences and the critical residues for G βγ stabilization and Na+ activation.

    CAS  PubMed  Google Scholar 

  13. Rohacs, T., Chen, J., Prestwich, G. D. & Logothetis, D. E. Distinct specificities of inwardly rectifying K+ channels for phosphoinositides. J. Biol. Chem. 274, 36065–36072 (1999).

    CAS  PubMed  Google Scholar 

  14. Rohacs, T. et al. Specificity of activation by phosphoinositides determines lipid regulation of Kir channels. Proc. Natl Acad. Sci. USA 100, 745–750 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ho, I. H. & Murrell-Lagnado, R. D. Molecular mechanism for sodium-dependent activation of G protein-gated K+ channels. J. Physiol. (Lond.) 520, 645–651 (1999).

    CAS  Google Scholar 

  16. Zeng, W. Z., Liou, H. H., Krishna, U. M., Falck, J. R. & Huang, C. L. Structural determinants and specificities for ROMK1–phosphoinositide interaction. Am. J. Physiol. Renal Physiol. 282, F826–F834 (2002).

    CAS  PubMed  Google Scholar 

  17. Krauter, T., Ruppersberg, J. P. & Baukrowitz, T. Phospholipids as modulators of KATP channels: distinct mechanisms for control of sensitivity to sulphonylureas, K+ channel openers, and ATP. Mol. Pharmacol. 59, 1086–1093 (2001).

    CAS  PubMed  Google Scholar 

  18. Rosenhouse-Dantsker, A. & Logothetis, D. E. Molecular characteristics of phosphoinositide binding. Pflugers Arch. 455, 45–53 (2007).

    CAS  PubMed  Google Scholar 

  19. Cukras, C. A., Jeliazkova, I. & Nichols, C. G. Structural and functional determinants of conserved lipid interaction domains of inward rectifying Kir6.2 channels. J. Gen. Physiol. 119, 581–591 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Lopes, C. M. et al. Alterations in conserved Kir channel–PIP2 interactions underlie channelopathies. Neuron 34, 933–944 (2002). This study carried out a systematic determination of the critical residues that are conserved among Kir channels and are essential for PIP 2 action. Many of these residues are loci for channel-mediated disease.

    CAS  PubMed  Google Scholar 

  21. Schulze, D., Krauter, T., Fritzenschaft, H., Soom, M. & Baukrowitz, T. Phosphatidylinositol 4,5-bisphosphate (PIP2) modulation of ATP and pH sensitivity in Kir channels. A tale of an active and a silent PIP2 site in the N terminus. J. Biol. Chem. 278, 10500–10505 (2003).

    CAS  PubMed  Google Scholar 

  22. Shyng, S. L., Cukras, C. A., Harwood, J. & Nichols, C. G. Structural determinants of PIP2 regulation of inward rectifier KATP channels. J. Gen. Physiol. 116, 599–608 (2000). This study carried out a systematic determination of the critical sites on the C termini of K ATP channels that mediate PIP 2 sensitivity.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Soom, M. et al. Multiple PIP2 binding sites in Kir2.1 inwardly rectifying potassium channels. FEBS Lett. 490, 49–53 (2001).

    CAS  PubMed  Google Scholar 

  24. Kuo, A., Domene, C., Johnson, L. N., Doyle, D. A. & Venien-Bryan, C. Two different conformational states of the KirBac3.1 potassium channel revealed by electron crystallography. Structure 13, 1463–1472 (2005).

    CAS  PubMed  Google Scholar 

  25. Nishida, M. & MacKinnon, R. Structural basis of inward rectification: cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8 Å resolution. Cell 111, 957–965 (2002).

    CAS  PubMed  Google Scholar 

  26. Pegan, S. et al. Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification. Nature Neurosci. 8, 279–287 (2005).

    CAS  PubMed  Google Scholar 

  27. Baukrowitz, T. et al. PIP2 and PIP as determinants for ATP inhibition of KATP channels. Science 282, 1141–1144 (1998).

    CAS  PubMed  Google Scholar 

  28. Xie, L. H., Horie, M. & Takano, M. Phospholipase C-linked receptors regulate the ATP-sensitive potassium channel by means of phosphatidylinositol 4,5-bisphosphate metabolism. Proc. Natl Acad. Sci. USA 96, 15292–15297 (1999). This paper provided the first published evidence that the muscarinic-receptor-mediated suppression of K+ channel currents is due to depletion of PIP 2 . Pharmacological blockade of PLC activity, and of phosphoinositide kinases, is used in mammalian cells to prevent current suppression or its recovery after receptor stimulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ribalet, B., John, S. A., Xie, L. H. & Weiss, J. N. Regulation of the ATP-sensitive K channel Kir6.2 by ATP and PIP2 . J. Mol. Cell. Cardiol. 39, 71–77 (2005).

    CAS  PubMed  Google Scholar 

  30. MacGregor, G. G. et al. Nucleotides and phospholipids compete for binding to the C terminus of KATP channels. Proc. Natl Acad. Sci. USA 99, 2726–2731 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Loussouarn, G., Pike, L. J., Ashcroft, F. M., Makhina, E. N. & Nichols, C. G. Dynamic sensitivity of ATP-sensitive K+ channels to ATP. J. Biol. Chem. 276, 29098–29103 (2001).

    CAS  PubMed  Google Scholar 

  32. Sui, J. L., Chan, K. W. & Logothetis, D. E. Na+ activation of the muscarinic K+ channel by a G-protein-independent mechanism. J. Gen. Physiol. 108, 381–391 (1996).

    CAS  PubMed  Google Scholar 

  33. Sui, J. L., Petit-Jacques, J. & Logothetis, D. E. Activation of the atrial KACh channel by the βγ subunits of G proteins or intracellular Na+ ions depends on the presence of phosphatidylinositol phosphates. Proc. Natl Acad. Sci. USA 95, 1307–1312 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. He, C. et al. Identification of critical residues controlling G protein-gated inwardly rectifying K+ channel activity through interactions with the βγ subunits of G proteins. J. Biol. Chem. 277, 6088–6096 (2002).

    CAS  PubMed  Google Scholar 

  35. Liou, H. H., Zhou, S. S. & Huang, C. L. Regulation of ROMK1 channel by protein kinase A via a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. Proc. Natl Acad. Sci. USA 96, 5820–5825 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Zeng, W. Z., Li, X. J., Hilgemann, D. W. & Huang, C. L. Protein kinase C inhibits ROMK1 channel activity via a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. J. Biol. Chem. 278, 16852–16856 (2003).

    CAS  PubMed  Google Scholar 

  37. Sohn, J. W. et al. Receptor-specific inhibition of GABAB-activated K+ currents by muscarinic and metabotropic glutamate receptors in immature rat hippocampus. J. Physiol. (Lond.) 580, 411–422 (2007).

    CAS  Google Scholar 

  38. Du, X. et al. Characteristic interactions with phosphatidylinositol 4,5-bisphosphate determine regulation of Kir channels by diverse modulators. J. Biol. Chem. 279, 37271–37281 (2004).

    CAS  PubMed  Google Scholar 

  39. Keselman, I., Fribourg, M., Felsenfeld, D. P. & Logothetis, D. E. Mechanism of PLC-mediated Kir3 current inhibition. Channels 1, 113–123 (2007).

    PubMed  Google Scholar 

  40. Lopes, C. M. B. et al. Protein kinase A modulates PLC-dependent regulation and PIP2-sensitivity of K+ channels. Channels 1, 124–134 (2007).

    PubMed  Google Scholar 

  41. Giebisch, G. Renal potassium transport: mechanisms and regulation. Am. J. Physiol. 274, F817–F833 (1998).

    CAS  PubMed  Google Scholar 

  42. Leung, Y. M., Zeng, W. Z., Liou, H. H., Solaro, C. R. & Huang, C. L. Phosphatidylinositol 4,5-bisphosphate and intracellular pH regulate the ROMK1 potassium channel via separate but interrelated mechanisms. J. Biol. Chem. 275, 10182–10189 (2000).

    CAS  PubMed  Google Scholar 

  43. Rapedius, M. et al. Structural and functional analysis of the putative pH sensor in the Kir1.1 (ROMK) potassium channel. EMBO Rep. 7, 611–616 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Oliver, D. et al. Functional conversion between A-type and delayed rectifier K+ channels by membrane lipids. Science 304, 265–270 (2004).

    CAS  PubMed  Google Scholar 

  45. Meyer, T. et al. Depletion of phosphatidylinositol 4,5-bisphosphate by activation of phospholipase C-coupled receptors causes slow inhibition but not desensitization of G protein-gated inward rectifier K+ current in atrial myocytes. J. Biol. Chem. 276, 5650–5658 (2001).

    CAS  PubMed  Google Scholar 

  46. Stauffer, T. P., Ahn, S. & Meyer, T. Receptor-induced transient reduction in plasma membrane PtdIns(4,5)P2 concentration monitored in living cells. Curr. Biol. 8, 343–346 (1998). In this study, a useful and widely used optical probe was developed for the monitoring of PIP 2 hydrolysis in individual living cells.

    CAS  PubMed  Google Scholar 

  47. Willars, G. B., Nahorski, S. R. & Challiss, R. A. Differential regulation of muscarinic acetylcholine receptor-sensitive polyphosphoinositide pools and consequences for signaling in human neuroblastoma cells. J. Biol. Chem. 273, 5037–5046 (1998).

    CAS  PubMed  Google Scholar 

  48. Zaika, O. et al. Angiotensin II regulates neuronal excitability via phosphatidylinositol 4,5-bisphosphate-dependent modulation of Kv7 (M-type) K+ channels. J. Physiol. (Lond.) 575, 49–67 (2006).

    CAS  Google Scholar 

  49. Horowitz, L. F. et al. Phospholipase C in living cells: activation, inhibition, Ca2+ requirement, and regulation of M current. J. Gen. Physiol. 126, 243–262 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Li, Y., Gamper, N., Hilgemann, D. W. & Shapiro, M. S. Regulation of Kv7 (KCNQ) K+ channel open probability by phosphatidylinositol (4,5)-bisphosphate. J. Neurosci. 25, 9825–9835 (2005). This study demonstrated, using single-channel recordings, that the divergent open probabilities among KCNQ channels are due to their differential apparent affinity for PIP 2 . It also used HPLC analysis to show that muscarinic stimulation can deplete PIP 2 in mammalian cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Lei, Q., Talley, E. M. & Bayliss, D. A. Receptor-mediated inhibition of G protein-coupled inwardly rectifying potassium channels involves Gαq family subunits, phospholipase C, and a readily diffusible messenger. J. Biol. Chem. 276, 16720–16730 (2001).

    CAS  PubMed  Google Scholar 

  52. Kobrinsky, E., Mirshahi, T., Zhang, H., Jin, T. & Logothetis, D. E. Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization. Nature Cell Biol. 2, 507–14 (2000).

    CAS  PubMed  Google Scholar 

  53. Cho, H. et al. Acetylcholine-induced phosphatidylinositol 4,5-bisphosphate depletion does not cause short-term desensitization of G protein-gated inwardly rectifying K+ current in mouse atrial myocytes. J. Biol. Chem. 277, 27742–27747 (2002).

    CAS  PubMed  Google Scholar 

  54. Braun, A. P., Fedida, D. & Giles, W. R. Activation of α1-adrenoceptors modulates the inwardly rectifying potassium currents of mammalian atrial myocytes. Pflugers Arch. 421, 431–439 (1992).

    CAS  PubMed  Google Scholar 

  55. Yamaguchi, H. et al. Dual effects of endothelins on the muscarinic K+ current in guinea pig atrial cells. Am. J. Physiol. 273, H1745–H1753 (1997).

    CAS  PubMed  Google Scholar 

  56. Cho, H., Youm, J. B., Ryu, S. Y., Earm, Y. E. & Ho, W. K. Inhibition of acetylcholine-activated K+ currents by U73122 is mediated by the inhibition of PIP2-channel interaction. Br. J. Pharmacol. 134, 1066–1072 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Haruna, T. et al. α1-adrenoceptor-mediated breakdown of phosphatidylinositol 4,5-bisphosphate inhibits pinacidil-activated ATP-sensitive K+ currents in rat ventricular myocytes. Circ. Res. 91, 232–239 (2002).

    CAS  PubMed  Google Scholar 

  58. Nasuhoglu, C. et al. Modulation of cardiac PIP2 by cardioactive hormones and other physiologically relevant interventions. Am. J. Physiol. Cell Physiol. 283, C223–C234 (2002).

    CAS  PubMed  Google Scholar 

  59. Cho, H. et al. Low mobility of phosphatidylinositol 4,5-bisphosphate underlies receptor specificity of Gq-mediated ion channel regulation in atrial myocytes. Proc. Natl Acad. Sci. USA 102, 15241–15246 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Pan, Z. et al. A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J. Neurosci. 26, 2599–2613 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Devaux, J. J., Kleopa, K. A., Cooper, E. C. & Scherer, S. S. KCNQ2 is a nodal K+ channel. J. Neurosci. 24, 1236–1244 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Cooper, E. C., Harrington, E., Jan, Y. N. & Jan, L. Y. M channel KCNQ2 subunits are localized to key sites for control of neuronal network oscillations and synchronization in mouse brain. J. Neurosci. 21, 9529–9540 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Passmore, G. M. et al. KCNQ/M currents in sensory neurons: significance for pain therapy. J. Neurosci. 23, 7227–7236 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang, H. S. et al. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282, 1890–1893 (1998).

    CAS  PubMed  Google Scholar 

  65. Suh, B. & Hille, B. Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis. Neuron 35, 507–520 (2002). This paper provided the first published evidence that PIP 2 depletion is the mystery signal that underlies the muscarinic suppression of native and cloned M currents. It focuses on the role of phosphoinositide kinases in current recovery.

    CAS  PubMed  Google Scholar 

  66. Ford, C. P., Stemkowski, P. L., Light, P. E. & Smith, P. A. Experiments to test the role of phosphatidylinositol 4,5-bisphosphate in neurotransmitter-induced M-channel closure in bullfrog sympathetic neurons. J. Neurosci. 23, 4931–4941 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhang, H. et al. PIP2 activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron 37, 963–975 (2003). This study showed that KCNQ channels in inside-out patches are regulated by PIP 2 , and that current inhibition by receptor stimulation correlates with PIP 2 hydrolysis.

    CAS  PubMed  Google Scholar 

  68. Barhanin, J. et al. KVLQT1 and lsK (minK) proteins associate to form the IKs cardiac potassium current. Nature 384, 78–80 (1996).

    CAS  PubMed  Google Scholar 

  69. Sanguinetti, M. C. et al. Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac IKs potassium channel. Nature 384, 80–83 (1996).

    CAS  PubMed  Google Scholar 

  70. Kubisch, C. et al. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 96, 437–446 (1999).

    CAS  PubMed  Google Scholar 

  71. Loussouarn, G. et al. Phosphatidylinositol-4,5-bisphosphate, PIP2, controls KCNQ1/KCNE1 voltage-gated potassium channels: a functional homology between voltage-gated and inward rectifier K+ channels. EMBO J. 22, 5412–5421 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Oancea, E., Teruel, M. N., Quest, A. F. & Meyer, T. Green fluorescent protein (GFP)-tagged cysteine-rich domains from protein kinase C as fluorescent indicators for diacylglycerol signaling in living cells. J. Cell Biol. 140, 485–498 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Winks, J. S. et al. Relationship between membrane phosphatidylinositol-4,5-bisphosphate and receptor-mediated inhibition of native neuronal M channels. J. Neurosci. 25, 3400–3413 (2005). This study provided quantitative calculations of changes in PIP 2 abundance in sympathetic neurons upon receptor stimulation or phosphoinositide kinase overexpression and correlated those changes with M-current suppression. Its findings suggested that some receptors in neurons can stimulate PIP 2 synthesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Raucher, D. et al. Phosphatidylinositol 4,5-bisphosphate functions as a second messenger that regulates cytoskeleton–plasma membrane adhesion. Cell 100, 221–228 (2000).

    CAS  PubMed  Google Scholar 

  75. Suh, B. C., Inoue, T., Meyer, T. & Hille, B. Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels. Science 314, 1454–1457 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Robbins, J., Marsh, S. J. & Brown, D. A. Probing the regulation of M (Kv7) potassium channels in intact neurons with membrane-targeted peptides. J. Neurosci. 26, 7950–7961 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. McLaughlin, S. & Murray, D. Plasma membrane phosphoinositide organization by protein electrostatics. Nature 438, 605–611 (2005).

    CAS  PubMed  Google Scholar 

  78. Xu, C., Watras, J. & Loew, L. M. Kinetic analysis of receptor-activated phosphoinositide turnover. J. Cell. Biol. 161, 779–791 (2003). This study used the Virtual Cell computer model of phosphoinositide metabolism, and PIP 2 hydrolysis probes in individual cells, to predict changes in PIP 2 and IP 3 levels upon receptor stimulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Suh, B. C., Horowitz, L. F., Hirdes, W., Mackie, K. & Hille, B. Regulation of KCNQ2/KCNQ3 current by G-protein cycling: the kinetics of receptor-mediated signaling by Gq . J. Gen. Physiol. 123, 663–683 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Li, Y., Gamper, N. & Shapiro, M. S. Single-channel analysis of KCNQ K+ channels reveals the mechanism of augmentation by a cysteine-modifying reagent. J. Neurosci. 24, 5079–5090 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Selyanko, A. A., Hadley, J. K. & Brown, D. A. Properties of single M-type KCNQ2/KCNQ3 potassium channels expressed in mammalian cells. J. Physiol. (Lond.) 534, 15–24. (2001).

    CAS  Google Scholar 

  82. Gamper, N., Li, Y. & Shapiro, M. S. Structural requirements for differential sensitivity of KCNQ K+ channels to modulation by Ca2+/calmodulin. Mol. Biol. Cell. 16, 3538–3551 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Gamper, N. & Shapiro, M. S. Calmodulin mediates Ca2+-dependent modulation of M-type K+ channels. J. Gen. Physiol. 122, 17–31 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Gamper, N., Stockand, J. D. & Shapiro, M. S. Subunit-specific modulation of KCNQ potassium channels by Src tyrosine kinase. J. Neurosci. 23, 84–95 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Hoshi, N. et al. AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists. Nature Neurosci. 6, 564–571 (2003).

    CAS  PubMed  Google Scholar 

  86. del Rio, E., Bevilacqua, J. A., Marsh, S. J., Halley, P. & Caulfield, M. P. Muscarinic M1 receptors activate phosphoinositide turnover and Ca2+ mobilisation in rat sympathetic neurones, but this signalling pathway does not mediate M-current inhibition. J. Physiol. (Lond.) 520, 101–111 (1999).

    CAS  Google Scholar 

  87. Gamper, N., Reznikov, V., Yamada, Y., Yang, J. & Shapiro, M. S. Phosphatidylinositol 4,5-bisphosphate signals underlie receptor-specific Gq/11-mediated modulation of N-type Ca2+ channels. J. Neurosci. 24, 10980–10992 (2004). This paper provided the first demonstration that neuronal N-type Ca2+ channels in sympathetic neurons are sensitive to receptor-mediated PIP 2 depletion. The authors also suggest a hypothesis for receptor-specific PIP 2 signalling.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Bofill-Cardona, E., Vartian, N., Nanoff, C., Freissmuth, M. & Boehm, S. Two different signaling mechanisms involved in the excitation of rat sympathetic neurons by uridine nucleotides. Mol. Pharmacol. 57, 1165–1172 (2000).

    CAS  PubMed  Google Scholar 

  89. Shapiro, M. S., Wollmuth, L. P. & Hille, B. Angiotensin II inhibits calcium and M current channels in rat sympathetic neurons via G proteins. Neuron 12, 1319–1329 (1994).

    CAS  PubMed  Google Scholar 

  90. Cruzblanca, H., Koh, D. S. & Hille, B. Bradykinin inhibits M current via phospholipase C and Ca2+ release from IP3-sensitive Ca2+ stores in rat sympathetic neurons. Proc. Natl Acad. Sci. USA 95, 7151–7156 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Delmas, P., Wanaverbecq, N., Abogadie, F. C., Mistry, M. & Brown, D. A. Signaling microdomains define the specificity of receptor-mediated InsP3 pathways in neurons. Neuron 34, 209–220 (2002). This paper contained a hypothesis that attempted to account for the differential signalling pathways that are triggered in sympathetic neurons by muscarinic and bradykinin receptors: the authors suggest that there is tight spatial colocalization of plasma membrane bradykinin receptors with intracellular IP 3 receptors, but no such colocalization for muscarinic receptors.

    CAS  PubMed  Google Scholar 

  92. Zaika, O., Tolstykh, G. P., Jaffe, D. B. & Shapiro, M. S. IP3 signals direct purinergic P2Y-receptor regulation of neuronal ion channels. J. Neurosci. 27, 8914–8926 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Koizumi, S. et al. Mechanisms underlying the neuronal calcium sensor-1-evoked enhancement of exocytosis in PC12 cells. J. Biol. Chem. 277, 30315–30324 (2002).

    CAS  PubMed  Google Scholar 

  94. Brown, D. A., Hughes, S. A., Marsh, S. J. & Tinker, A. Regulation of M(Kv7.2/7.3) channels in neurons by PIP2 and products of PIP2 hydrolysis: significance for receptor-mediated inhibition. J. Physiol. (Lond.) 582, 917–925 (2007).

    CAS  Google Scholar 

  95. Delmas, P. & Brown, D. A. Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nature Rev. Neurosci. 6, 850–862 (2005).

    CAS  Google Scholar 

  96. Delmas, P., Coste, B., Gamper, N. & Shapiro, M. S. Phosphoinositide lipid second messengers: new paradigms for calcium channel modulation. Neuron 47, 179–182 (2005).

    CAS  PubMed  Google Scholar 

  97. Hoshi, N., Langeberg, L. K. & Scott, J. D. Distinct enzyme combinations in AKAP signalling complexes permit functional diversity. Nature Cell Biol. 7, 1066–1073 (2005).

    CAS  PubMed  Google Scholar 

  98. Dell'Acqua, M. L., Faux, M. C., Thorburn, J., Thorburn, A. & Scott, J. D. Membrane-targeting sequences on AKAP79 bind phosphatidylinositol-4,5-bisphosphate. EMBO J. 17, 2246–2260 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Park, K. H. et al. Impaired KCNQ1–KCNE1 and phosphatidylinositol-4,5-bisphosphate interaction underlies the long QT syndrome. Circ. Res. 96, 730–739 (2005).

    CAS  PubMed  Google Scholar 

  100. Fink, M. et al. Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel. EMBO J. 15, 6854–6862 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Lesage, F. et al. TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure. EMBO J. 15, 1004–1011 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Duprat, F. et al. TASK, a human background K+ channel to sense external pH variations near physiological pH. EMBO J. 16, 5464–5471 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Patel, A. J., Lazdunski, M. & Honore, E. Lipid and mechano-gated 2P domain K+ channels. Curr. Opin. Cell Biol. 13, 422–428 (2001).

    CAS  PubMed  Google Scholar 

  104. Kim, D. Physiology and pharmacology of two-pore domain potassium channels. Curr. Pharm. Des. 11, 2717–2736 (2005).

    CAS  PubMed  Google Scholar 

  105. Plant, L. D., Rajan, S. & Goldstein, S. A. K2P channels and their protein partners. Curr. Opin. Neurobiol. 15, 326–333 (2005).

    CAS  PubMed  Google Scholar 

  106. Talley, E. M., Lei, Q., Sirois, J. E. & Bayliss, D. A. TASK-1, a two-pore domain K+ channel, is modulated by multiple neurotransmitters in motoneurons. Neuron 25, 399–410 (2000).

    CAS  PubMed  Google Scholar 

  107. Millar, J. A. et al. A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons. Proc. Natl Acad. Sci. USA 97, 3614–3618 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Mathie, A. Neuronal two-pore-domain potassium channels and their regulation by G protein-coupled receptors. J. Physiol. (Lond.) 578, 377–385 (2007).

    CAS  Google Scholar 

  109. Czirjak, G. & Enyedi, P. Targeting of calcineurin to an NFAT-like docking site is required for the calcium-dependent activation of the background K+ channel, TRESK. J. Biol. Chem. 281, 14677–14682 (2006).

    CAS  PubMed  Google Scholar 

  110. Chemin, J. et al. Mechanisms underlying excitatory effects of group I metabotropic glutamate receptors via inhibition of 2P domain K+ channels. EMBO J. 22, 5403–5411 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Chemin, J. et al. A phospholipid sensor controls mechanogating of the K+ channel TREK-1. EMBO J. 24, 44–53 (2005).

    CAS  PubMed  Google Scholar 

  112. Lopes, C. M. et al. PIP2 hydrolysis underlies agonist-induced inhibition and regulates voltage gating of two-pore domain K+ channels. J. Physiol. (Lond.) 564, 117–129 (2005). This paper suggested that TASK, TREK and TRAAK two-pore channels are sensitive to PIP 2 abundance and that PIP 2 depletion underlies current suppression by receptor stimulation.

    CAS  Google Scholar 

  113. Boyd, D. F., Millar, J. A., Watkins, C. S. & Mathie, A. The role of Ca2+ stores in the muscarinic inhibition of the K+ current IKSO in neonatal rat cerebellar granule cells. J. Physiol. (Lond.) 529, 321–331 (2000).

    CAS  Google Scholar 

  114. Chen, X. et al. Inhibition of a background potassium channel by Gq protein α-subunits. Proc. Natl Acad. Sci. USA 103, 3422–3427 (2006). This study suggested that the suppression of TASK two-pore channel currents by receptor stimulation is due to the direct interaction of the channels with G αq , rather than a result of PIP 2 depletion.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Veale, E. L. et al. Gαq-mediated regulation of TASK3 two-pore domain potassium channels: the role of protein kinase C. Mol. Pharmacol. 71, 1666–1675 (2007).

    CAS  PubMed  Google Scholar 

  116. Murbartian, J., Lei, Q., Sando, J. J. & Bayliss, D. A. Sequential phosphorylation mediates receptor- and kinase-induced inhibition of TREK-1 background potassium channels. J. Biol. Chem. 280, 30175–30184 (2005).

    CAS  PubMed  Google Scholar 

  117. Chemin, J. et al. Up- and down-regulation of the mechano-gated K2P channel TREK-1 by PIP2 and other membrane phospholipids. Pflugers Arch. 455, 97–103 (2007).

    CAS  PubMed  Google Scholar 

  118. Delmas, P., Crest, M. & Brown, D. A. Functional organization of PLC signaling microdomains in neurons. Trends Neurosci. 27, 41–47 (2004).

    CAS  PubMed  Google Scholar 

  119. Gamper, N. & Shapiro, M. S. Target-specific PIP2 signalling: how might it work? J. Physiol. (Lond.) 582, 967–975 (2007).

    CAS  Google Scholar 

  120. Ludwig, A., Zong, X., Jeglitsch, M., Hofmann, F. & Biel, M. A family of hyperpolarization-activated mammalian cation channels. Nature 393, 587–591 (1998).

    CAS  PubMed  Google Scholar 

  121. Santoro, B. et al. Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. Cell 93, 717–729 (1998).

    CAS  PubMed  Google Scholar 

  122. Magee, J. C. & Carruth, M. Dendritic voltage-gated ion channels regulate the action potential firing mode of hippocampal CA1 pyramidal neurons. J. Neurophysiol. 82, 1895–1901 (1999).

    CAS  PubMed  Google Scholar 

  123. Pape, H. C. & McCormick, D. A. Noradrenaline and serotonin selectively modulate thalamic burst firing by enhancing a hyperpolarization-activated cation current. Nature 340, 715–718 (1989).

    CAS  PubMed  Google Scholar 

  124. Zolles, G. et al. Pacemaking by HCN channels requires interaction with phosphoinositides. Neuron 52, 1027–1036 (2006).

    CAS  PubMed  Google Scholar 

  125. Pian, P., Bucchi, A., Robinson, R. B. & Siegelbaum, S. A. Regulation of gating and rundown of HCN hyperpolarization-activated channels by exogenous and endogenous PIP2 . J. Gen. Physiol. 128, 593–604 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Pian, P., Bucchi, A., Decostanzo, A., Robinson, R. B. & Siegelbaum, S. A. Modulation of cyclic nucleotide-regulated HCN channels by PIP2 and receptors coupled to phospholipase C. Pflugers Arch. 455, 125–145 (2007).

    CAS  PubMed  Google Scholar 

  127. Schledermann, W., Wulfsen, I., Schwarz, J. R. & Bauer, C. K. Modulation of rat erg1, erg2, erg3 and HERG K+ currents by thyrotropin-releasing hormone in anterior pituitary cells via the native signal cascade. J. Physiol. (Lond.) 532, 143–163 (2001).

    CAS  Google Scholar 

  128. Hirdes, W., Horowitz, L. F. & Hille, B. Muscarinic modulation of erg potassium current. J. Physiol. (Lond.) 559, 67–84 (2004).

    CAS  Google Scholar 

  129. Bian, J., Cui, J. & McDonald, T. V. HERG K+ channel activity is regulated by changes in phosphatidyl inositol 4,5-bisphosphate. Circ. Res. 89, 1168–1176 (2001).

    CAS  PubMed  Google Scholar 

  130. Bian, J. S., Kagan, A. & McDonald, T. V. Molecular analysis of PIP2 regulation of HERG and IKr . Am. J. Physiol. Heart Circ. Physiol. 287, H2154–H2163 (2004).

    CAS  PubMed  Google Scholar 

  131. Bian, J. S. & McDonald, T. V. Phosphatidylinositol 4,5-bisphosphate interactions with the HERG K+ channel. Pflugers Arch. 455, 105–113 (2007).

    CAS  PubMed  Google Scholar 

  132. Catterall, W. A. Structure and regulation of voltage-gated Ca2+ channels. Annu. Rev. Cell. Dev. Biol. 16, 521–555 (2000).

    CAS  PubMed  Google Scholar 

  133. Wu, L., Bauer, C. S., Zhen, X. G., Xie, C. & Yang, J. Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2 . Nature 419, 947–952 (2002). This paper provided the first demonstration that voltage-gated Ca2+ channels are PIP 2 sensitive.

    CAS  PubMed  Google Scholar 

  134. Michailidis, I. E., Zhang, Y. & Yang, J. The lipid connection — regulation of voltage-gated Ca2+ channels by phosphoinositides. Pflugers Arch. 455, 147–155 (2007).

    CAS  PubMed  Google Scholar 

  135. Bean, B. P. Neurotransmitter inhibition of neuronal calcium currents by changes in channel voltage dependence. Nature 340, 153–156 (1989).

    CAS  PubMed  Google Scholar 

  136. Herlitze, S., Hockerman, G. H., Scheuer, T. & Catterall, W. A. Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel α1A subunit. Proc. Natl Acad. Sci. USA 94, 1512–1516 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Ikeda, S. R. Voltage-dependent modulation of N-type calcium channels by G-protein βγ subunits. Nature 380, 255–258 (1996).

    CAS  PubMed  Google Scholar 

  138. Raingo, J., Castiglioni, A. J. & Lipscombe, D. Alternative splicing controls G protein-dependent inhibition of N-type calcium channels in nociceptors. Nature Neurosci. 10, 285–292 (2007).

    CAS  PubMed  Google Scholar 

  139. Diverse-Pierluissi, M., Remmers, A. E., Neubig, R. R. & Dunlap, K. Novel form of crosstalk between G protein and tyrosine kinase pathways. Proc. Natl Acad. Sci. USA 94, 5417–5421 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Rousset, M., Cens, T., Gouin-Charnet, A., Scamps, F. & Charnet, P. Ca2+ and phosphatidylinositol 4,5-bisphosphate stabilize a Gβγ-sensitive state of CaV2 Ca2+ channels. J. Biol. Chem. 279, 14619–14630 (2004).

    CAS  PubMed  Google Scholar 

  141. Zhen, X. G. et al. A single amino acid mutation attenuates rundown of voltage-gated calcium channels. FEBS Lett. 580, 5733–5738 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Hildebrand, M. E. et al. Selective inhibition of Cav3.3 T-type calcium channels by Gaq/11-coupled muscarinic acetylcholine receptors. J. Biol. Chem. 282, 21043–21055 (2007).

    CAS  PubMed  Google Scholar 

  143. Bannister, R. A., Melliti, K. & Adams, B. A. Differential modulation of CaV2.3 Ca2+ channels by Gαq/11-coupled muscarinic receptors. Mol. Pharmacol. 65, 381–388 (2004).

    CAS  PubMed  Google Scholar 

  144. Liu, L., Barrett, C. F. & Rittenhouse, A. R. Arachidonic acid both inhibits and enhances whole cell calcium currents in rat sympathetic neurons. Am. J. Physiol. Cell Physiol. 280, C1293–C1305 (2001).

    CAS  PubMed  Google Scholar 

  145. Liu, L. & Rittenhouse, A. R. Arachidonic acid mediates muscarinic inhibition and enhancement of N-type Ca2+ current in sympathetic neurons. Proc. Natl Acad. Sci. USA 100, 295–300 (2003).

    CAS  PubMed  Google Scholar 

  146. Liu, L. et al. M1 muscarinic receptors inhibit L-type Ca2+ current and M-current by divergent signal transduction cascades. J. Neurosci. 26, 11588–11598 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Lechner, S. G., Hussl, S., Schicker, K. W., Drobny, H. & Boehm, S. Presynaptic inhibition via a phospholipase C- and phosphatidylinositol bisphosphate-dependent regulation of neuronal Ca2+ channels. Mol. Pharmacol. 68, 1387–1396 (2005).

    CAS  PubMed  Google Scholar 

  148. Lu, Z., Jiang, Y. P., Ballou, L. M., Cohen, I. S. & Lin, R. Z. Gαq inhibits cardiac L-type Ca2+ channels through phosphatidylinositol 3-kinase. J. Biol. Chem. 280, 40347–40354 (2005).

    CAS  PubMed  Google Scholar 

  149. Blair, L. A. & Marshall, J. IGF-1 modulates N and L calcium channels in a PI 3-kinase-dependent manner. Neuron 19, 421–429 (1997).

    CAS  PubMed  Google Scholar 

  150. Gao, L., Blair, L. A., Salinas, G. D., Needleman, L. A. & Marshall, J. Insulin-like growth factor-1 modulation of CaV1.3 calcium channels depends on Ca2+ release from IP3-sensitive stores and calcium/calmodulin kinase II phosphorylation of the α1 subunit EF hand. J. Neurosci. 26, 6259–6268 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Viard, P. et al. PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane. Nature Neurosci. 7, 939–946 (2004).

    CAS  PubMed  Google Scholar 

  152. Gribkoff, V. K. The role of voltage-gated calcium channels in pain and nociception. Semin. Cell Dev. Biol. 17, 555–564 (2006).

    CAS  PubMed  Google Scholar 

  153. Patwardhan, A. M. et al. Bradykinin-induced functional competence and trafficking of the δ-opioid receptor in trigeminal nociceptors. J. Neurosci. 25, 8825–8832 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Patwardhan, A. M. et al. PAR-2 agonists activate trigeminal nociceptors and induce functional competence in the delta opioid receptor. Pain 125, 114–124 (2006).

    CAS  PubMed  Google Scholar 

  155. Ruan, H. Z. & Burnstock, G. Localisation of P2Y1 and P2Y4 receptors in dorsal root, nodose and trigeminal ganglia of the rat. Histochem. Cell Biol. 120, 415–426 (2003).

    CAS  PubMed  Google Scholar 

  156. Miljanich, G. P. Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr. Med. Chem. 11, 3029–3040 (2004).

    CAS  PubMed  Google Scholar 

  157. Rohacs, T. Regulation of TRP channels by PIP2 . Pflugers Arch. 453, 753–762 (2007).

    CAS  PubMed  Google Scholar 

  158. Hardie, R. C. TRP channels and lipids: from Drosophila to mammalian physiology. J. Physiol. (Lond.) 578, 9–24 (2007).

    CAS  Google Scholar 

  159. Voets, T. & Nilius, B. Modulation of TRPs by PIPs. J. Physiol. (Lond.) 582, 939–944 (2007).

    CAS  Google Scholar 

  160. Runnels, L. W., Yue, L. & Clapham, D. E. The TRPM7 channel is inactivated by PIP2 hydrolysis. Nature Cell Biol. 4, 329–336 (2002). The authors of this study showed that, in native cardiac cells and heterologous expression systems, G q/11 - or tyrosine kinase-coupled receptors potently inhibit the activity of TRPM7 through PIP 2 depletion. This study provided the first direct demonstration that TRPM-channel activity requires membrane PIP 2.

    CAS  PubMed  Google Scholar 

  161. Liu, B. & Qin, F. Functional control of cold- and menthol-sensitive TRPM8 ion channels by phosphatidylinositol 4,5-bisphosphate. J. Neurosci. 25, 1674–1681 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Rohacs, T., Lopes, C. M., Michailidis, I. & Logothetis, D. E. PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain. Nature Neurosci. 8, 626–634 (2005). The authors of this paper suggested a central role for PIP 2 in the activation of TRPM8 channels by cold and menthol: Ca2+-dependent PIP 2 depletion is suggested as a mechanism for the desensitization of TRPM8. Using site-directed mutagenesis, the authors identified positive residues in the highly conserved TRP box of TRPM channels that might be important for the channel–PIP 2 interaction.

    CAS  PubMed  Google Scholar 

  163. Liu, D. & Liman, E. R. Intracellular Ca2+ and the phospholipid PIP2 regulate the taste transduction ion channel TRPM5. Proc. Natl Acad. Sci. USA 100, 15160–15165 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Zhang, Z., Okawa, H., Wang, Y. & Liman, E. R. Phosphatidylinositol 4,5-bisphosphate rescues TRPM4 channels from desensitization. J. Biol. Chem. 280, 39185–39192 (2005).

    CAS  PubMed  Google Scholar 

  165. Nilius, B. et al. The Ca2+-activated cation channel TRPM4 is regulated by phosphatidylinositol 4,5-biphosphate. EMBO J. 25, 467–478 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Bautista, D. M. et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124, 1269–1282 (2006).

    CAS  PubMed  Google Scholar 

  167. Dai, Y. et al. Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. J. Clin. Invest. 117, 1979–1987 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Ma, W. & Quirion, R. Inflammatory mediators modulating the transient receptor potential vanilloid 1 receptor: therapeutic targets to treat inflammatory and neuropathic pain. Expert Opin. Ther. Targets 11, 307–320 (2007).

    PubMed  Google Scholar 

  169. Patwardhan, A. M. et al. The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin. Proc. Natl Acad. Sci. USA 103, 11393–11398 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Chuang, H. H. et al. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411, 957–962 (2001).

    CAS  PubMed  Google Scholar 

  171. Prescott, E. D. & Julius, D. A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science 300, 1284–1288 (2003).

    CAS  PubMed  Google Scholar 

  172. Lukacs, V. et al. Dual regulation of TRPV1 by phosphoinositides. J. Neurosci. 27, 7070–7080 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Stein, A. T., Ufret-Vincenty, C. A., Hua, L., Santana, L. F. & Gordon, S. E. Phosphoinositide 3-kinase binds to TRPV1 and mediates NGF-stimulated TRPV1 trafficking to the plasma membrane. J. Gen. Physiol. 128, 509–522 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Akopian, A. N., Ruparel, N. B., Jeske, N. A. & Hargreaves, K. M. TRPA1 desensitization in sensory neurons is agonist-dependent and regulated by TRPV1-directed internalization. J. Physiol. (Lond.) 583, 175–193 (2007).

    CAS  Google Scholar 

  175. Amadesi, S. et al. Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia. J. Neurosci. 24, 4300–4312 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Dai, Y. et al. Proteinase-activated receptor 2-mediated potentiation of transient receptor potential vanilloid subfamily 1 activity reveals a mechanism for proteinase-induced inflammatory pain. J. Neurosci. 24, 4293–4299 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Liu, B., Zhang, C. & Qin, F. Functional recovery from desensitization of vanilloid receptor TRPV1 requires resynthesis of phosphatidylinositol 4,5-bisphosphate. J. Neurosci. 25, 4835–4843 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Jeske, N. A. et al. Cannabinoid WIN 55,212-2 regulates TRPV1 phosphorylation in sensory neurons. J. Biol. Chem. 281, 32879–32890 (2006).

    CAS  PubMed  Google Scholar 

  179. Lee, J., Cha, S. K., Sun, T. J. & Huang, C. L. PIP2 activates TRPV5 and releases its inhibition by intracellular Mg2+. J. Gen. Physiol. 126, 439–451 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Chyb, S., Raghu, P. & Hardie, R. C. Polyunsaturated fatty acids activate the Drosophila light-sensitive channels TRP and TRPL. Nature 397, 255–259 (1999). In this paper, the authors studied the molecular pathways of PLC signalling in the mechanism of light transduction in Drosophila . They showed that both light-sensitive channels of the Drosophila photoreceptors (TRP and TRPL) are reversibly activated by the products of PIP 2 metabolism (DAG and PUFAs).

    CAS  PubMed  Google Scholar 

  181. Estacion, M., Sinkins, W. G. & Schilling, W. P. Regulation of Drosophila transient receptor potential-like (TrpL) channels by phospholipase C-dependent mechanisms. J. Physiol. (Lond.) 530, 1–19 (2001).

    CAS  Google Scholar 

  182. Hardie, R. C. et al. Calcium influx via TRP channels is required to maintain PIP2 levels in Drosophila photoreceptors. Neuron 30, 149–159 (2001).

    CAS  PubMed  Google Scholar 

  183. Montell, C. Visual transduction in Drosophila. Annu. Rev. Cell Dev. Biol. 15, 231–268 (1999).

    CAS  PubMed  Google Scholar 

  184. Lindemann, B. Receptors and transduction in taste. Nature 413, 219–225 (2001).

    CAS  PubMed  Google Scholar 

  185. Perez, C. A. et al. A transient receptor potential channel expressed in taste receptor cells. Nature Neurosci. 5, 1169–1176 (2002).

    CAS  PubMed  Google Scholar 

  186. Zhang, Z. H. et al. Inhibitory effects of pimozide on cloned and native voltage-gated potassium channels. Brain Res. Mol. Brain Res. 115, 29–38 (2003).

    CAS  PubMed  Google Scholar 

  187. Niggli, V., Adunyah, E. S. & Carafoli, E. Acidic phospholipids, unsaturated fatty acids, and limited proteolysis mimic the effect of calmodulin on the purified erythrocyte Ca2+ - ATPase. J. Biol. Chem. 256, 8588–8592 (1981).

    CAS  PubMed  Google Scholar 

  188. Vemuri, R. & Philipson, K. D. Phospholipid composition modulates the Na+–Ca2+ exchange activity of cardiac sarcolemma in reconstituted vesicles. Biochim. Biophys. Acta 937, 258–268 (1988).

    CAS  PubMed  Google Scholar 

  189. Choquette, D. et al. Regulation of plasma membrane Ca2+ ATPases by lipids of the phosphatidylinositol cycle. Biochem. Biophys. Res. Commun. 125, 908–915 (1984).

    CAS  PubMed  Google Scholar 

  190. Hilgemann, D. W. Regulation and deregulation of cardiac Na+–Ca2+ exchange in giant excised sarcolemmal membrane patches. Nature 344, 242–245 (1990).

    CAS  PubMed  Google Scholar 

  191. Posada, V., Beauge, L. & Berberian, G. Maximal Ca2+i stimulation of cardiac Na+/Ca2+ exchange requires simultaneous alkalinization and binding of PtdIns-4,5-P2 to the exchanger. Biol. Chem. 388, 281–288 (2007).

    CAS  PubMed  Google Scholar 

  192. Aharonovitz, O. et al. Intracellular pH regulation by Na+/H+ exchange requires phosphatidylinositol 4,5-bisphosphate. J. Cell Biol. 150, 213–224 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. He, Z., Feng, S., Tong, Q., Hilgemann, D. W. & Philipson, K. D. Interaction of PIP2 with the XIP region of the cardiac Na/Ca exchanger. Am. J. Physiol. Cell Physiol. 278, C661–C666 (2000).

    CAS  PubMed  Google Scholar 

  194. Beauge, L., Asteggiano, C. & Berberian, G. Regulation of phosphatidylinositol-4,5-biphosphate bound to the bovine cardiac Na+/Ca2+ exchanger. Ann. NY Acad. Sci. 976, 288–299 (2002).

    CAS  PubMed  Google Scholar 

  195. Rasgado-Flores, H. & Gonzalez-Serratos, H. Plasmalemmal transport of magnesium in excitable cells. Front. Biosci. 5, D866–D879 (2000).

    CAS  PubMed  Google Scholar 

  196. Yaradanakul, A. et al. Dual control of cardiac Na/Ca exchange by PIP2: electrophysiological analysis of direct and indirect mechanisms. J. Physiol. (Lond.) 582, 991–1010 (2007).

    CAS  Google Scholar 

  197. Kellenberger, S. & Schild, L. Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiol. Rev. 82, 735–767 (2002).

    CAS  PubMed  Google Scholar 

  198. van Zeijl, L. et al. Regulation of connexin43 gap junctional communication by phosphatidylinositol 4,5-bisphosphate. J. Cell Biol. 177, 881–891 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Hirono, M., Denis, C. S., Richardson, G. P. & Gillespie, P. G. Hair cells require phosphatidylinositol 4,5-bisphosphate for mechanical transduction and adaptation. Neuron 44, 309–320 (2004).

    CAS  PubMed  Google Scholar 

  200. Zhainazarov, A. B. & Ache, B. W. Effects of phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 4-phosphate on a Na+-gated nonselective cation channel. J. Neurosci. 19, 2929–2937 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Womack, K. B. et al. Do phosphatidylinositides modulate vertebrate phototransduction? J. Neurosci. 20, 2792–2799 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Zhainazarov, A. B., Spehr, M., Wetzel, C. H., Hatt, H. & Ache, B. W. Modulation of the olfactory CNG channel by Ptdlns(3,4,5)P3 . J. Membr. Biol. 201, 51–57 (2004).

    CAS  PubMed  Google Scholar 

  203. Michailidis, I. E. et al. Phosphatidylinositol-4,5-bisphosphate regulates NMDA receptor activity through α-actinin. J. Neurosci. 27, 5523–5532 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Zhao, Q., Logothetis, D. E. & Seguela, P. Regulation of ATP-gated P2X receptors by phosphoinositides. Pflugers Arch. 455, 181–185 (2007).

    CAS  PubMed  Google Scholar 

  205. Balla, T. Imaging and manipulating phosphoinositides in living cells. J. Physiol. (Lond.) 585, 927–937 (2007).

    Google Scholar 

  206. Nasuhoglu, C. et al. Nonradioactive analysis of phosphatidylinositides and other anionic phospholipids by anion-exchange high-performance liquid chromatography with suppressed conductivity detection. Anal. Biochem. 301, 243–254 (2002).

    CAS  PubMed  Google Scholar 

  207. Varnai, P., Thyagarajan, B., Rohacs, T. & Balla, T. Rapidly inducible changes in phosphatidylinositol 4,5-bisphosphate levels influence multiple regulatory functions of the lipid in intact living cells. J. Cell Biol. 175, 377–382 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Thomas, A. M., Brown, S. G., Leaney, J. L. & Tinker, A. Differential phosphoinositide binding to components of the G protein-gated K+ channel. J. Membr. Biol. 211, 43–53 (2006).

    CAS  PubMed  Google Scholar 

  209. Takenawa, T. & Itoh, T. Phosphoinositides, key molecules for regulation of actin cytoskeletal organization and membrane traffic from the plasma membrane. Biochim. Biophys. Acta 1533, 190–206 (2001).

    CAS  PubMed  Google Scholar 

  210. Cho, H., Kim, Y. A. & Ho, W. K. Phosphate number and acyl chain length determine the subcellular location and lateral mobility of phosphoinositides. Mol. Cells 22, 97–103 (2006).

    CAS  PubMed  Google Scholar 

  211. Kunzelmann, K. et al. Purinergic inhibition of the epithelial Na+ transport via hydrolysis of PIP2 . FASEB J. 19, 142–143 (2005).

    CAS  PubMed  Google Scholar 

  212. Ma, H. P., Saxena, S. & Warnock, D. G. Anionic phospholipids regulate native and expressed epithelial sodium channel (ENaC). J. Biol. Chem. 277, 7641–7644 (2002). This was the first paper (followed immediately by reference 213) to demonstrate acute enhancement of the activity of native ENaCs by PIP 2 and PIP 3.

    CAS  PubMed  Google Scholar 

  213. Yue, G., Malik, B., Yue, G. & Eaton, D. C. Phosphatidylinositol 4,5-bisphosphate (PIP2) stimulates epithelial sodium channel activity in A6 cells. J. Biol. Chem. 277, 11965–11969 (2002).

    CAS  PubMed  Google Scholar 

  214. Tong, Q. & Stockand, J. D. Receptor tyrosine kinases mediate epithelial Na+ channel inhibition by epidermal growth factor. Am. J. Physiol. Renal Physiol. 288, F150–F161 (2005).

    CAS  PubMed  Google Scholar 

  215. Tong, Q., Gamper, N., Medina, J. L., Shapiro, M. S. & Stockand, J. D. Direct activation of the epithelial Na+ channel by phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate produced by phosphoinositide 3-OH kinase. J. Biol. Chem. 279, 22654–22663 (2004).

    CAS  PubMed  Google Scholar 

  216. Pochynyuk, O., Staruschenko, A., Tong, Q., Medina, J. & Stockand, J. D. Identification of a functional phosphatidylinositol 3,4,5-trisphosphate binding site in the epithelial Na+ channel. J. Biol. Chem. 280, 37565–37571 (2005).

    CAS  PubMed  Google Scholar 

  217. Staruschenko, A., Pochynyuk, O., Vandewalle, A., Bugaj, V. & Stockand, J. D. Acute regulation of the epithelial Na+ channel by phosphatidylinositide 3-OH kinase signaling in native collecting duct principal cells. J. Am. Soc. Nephrol. 18, 1652–1661 (2007).

    CAS  PubMed  Google Scholar 

  218. Pochynyuk, O., Tong, Q., Staruschenko, A. & Stockand, J. D. Binding and direct activation of the epithelial Na+ channel (ENaC) by phosphatidylinositides. J. Physiol. (Lond.) 580, 365–372 (2007).

    CAS  Google Scholar 

  219. Pochynyuk, O. et al. Rapid translocation and insertion of the epithelial Na+ channel in response to RhoA signaling. J. Biol. Chem. 281, 26520–26527 (2006).

    CAS  PubMed  Google Scholar 

  220. Lang, F. et al. (Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol. Rev. 86, 1151–1178 (2006).

    CAS  PubMed  Google Scholar 

  221. Jasti, J. Furukawa, H. Gonzales, E. B. & Gouaux, E. Structure of acid-sensing ion channel 1 at 1.9 Å resolution and low pH. Nature 449, 316–324 (2007).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work in the laboratories of the authors was supported by grants NIH R01 NS043394 and AHA Grant-in-Aid 0755071Y (M.S.S.) and Welcome Trust grants 080593 and 080833 (N.G.).

Author information

Authors and Affiliations

Authors

Related links

Related links

FURTHER INFORMATION

Mark S. Shapiro's homepage

Nikita Gamper's homepage

Glossary

Apparent affinity

A functional measure of the relative strength with which a ligand acts on its presumed substrate. No biochemical binding affinity is actually measured.

Inwardly rectifying K+ channels

A diverse family of K+ channels that typically allow inward movement of K+ preferentially to outward movement. They all possess two transmembrane domains and a single pore domain. They lack a voltage-sensor domain; instead, their fast gating is controlled by blocking particles.

Crystal structure

The image of a protein's structure that is obtained by carrying out X-ray diffraction on crystalline forms of the given protein. The resolution is usually at the low angstrom (<5Å) range.

Microdomains

Subcellular domains of plasma membrane and associated proteins of no more than several μm2 that are hypothesized to cluster signalling molecules together to achieve specificity in signalling pathways.

M current

A non-inactivating, voltage-dependent K+ current generated by KCNQ subunits that has a large role in controlling neuronal excitability. Its name comes from its discovery as a K+ conductance that is depressed by the stimulation of muscarinic acetylcholine receptors in sympathetic ganglion neurons.

Open probability

The probability of an individual ion channel protein being in the open state under a given condition, observed as the fraction of the time that an ionic current is flowing. The value can be between zero and one.

Pleckstrin Homology domains

(PH domains). Protein domains that can bind to phosphoinositides in biological membranes and to proteins, such as the βγ-subunits of heterotrimeric G proteins, and protein kinase C. Through these interactions, PH domains have roles in recruiting proteins to different membranes or to appropriate cellular compartments.

Peripheral sensitization

The hyperexcitability of peripheral sensory neurons that develops upon inflammation and underlies the increased sensitivity to normally non-painful (allodynia) or slightly painful (hyperalgesia) stimuli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gamper, N., Shapiro, M. Regulation of ion transport proteins by membrane phosphoinositides. Nat Rev Neurosci 8, 921–934 (2007). https://doi.org/10.1038/nrn2257

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2257

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing